Natural products and Pharma 2011: strategic changes spur new opportunities.

Although natural products have been marginalized by major pharmaceutical companies over the last 20-30 years, the changing landscape of drug discovery now favors a greatly enhanced role for Nature's privileged structures. Screening for drug leads in phenotypic screens provides the best opportunity to realize the value of natural products. Advances in total synthesis, especially function-oriented syntheses and biosynthetic technologies offer new avenues for the medicinal chemical optimization of biologically active secondary metabolites. Genomic research has given new insights into biosynthetic processes as well as providing evidence that a wealth of unrealized biosynthetic potential remains to be explored. As Pharma strives to develop innovative and highly effective new drugs, natural products will be increasingly valued as sources of novel leads whose further development will be expedited by emerging technologies.

[1]  Stephen P. Hale,et al.  The exploration of macrocycles for drug discovery — an underexploited structural class , 2008, Nature Reviews Drug Discovery.

[2]  E. Graziani,et al.  Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs. , 2009, Natural product reports.

[3]  V. Goldmacher,et al.  Antibody-drug conjugates: using monoclonal antibodies for delivery of cytotoxic payloads to cancer cells. , 2011, Therapeutic delivery.

[4]  Arnold L. Demain,et al.  From natural products discovery to commercialization: a success story , 2006, Journal of Industrial Microbiology and Biotechnology.

[5]  Michelle R. Arkin,et al.  Small-molecule inhibitors of protein–protein interactions: progressing towards the dream , 2004, Nature Reviews Drug Discovery.

[6]  D. Uemura,et al.  Halichondrins - antitumor polyether macrolides from a marine sponge , 1986 .

[7]  I. Kola,et al.  Can the pharmaceutical industry reduce attrition rates? , 2004, Nature Reviews Drug Discovery.

[8]  Melissa M. Wagenaar,et al.  Pre-fractionated Microbial Samples – The Second Generation Natural Products Library at Wyeth , 2008, Molecules.

[9]  A. Hopkins Network pharmacology: the next paradigm in drug discovery. , 2008, Nature chemical biology.

[10]  Michael Goodman Pharmaceutical industry financial performance , 2009, Nature Reviews Drug Discovery.

[11]  Michael A Fischbach,et al.  Natural products version 2.0: connecting genes to molecules. , 2010, Journal of the American Chemical Society.

[12]  Lynda Tremblay,et al.  Macrocyclic ketone analogues of halichondrin B. , 2004, Bioorganic & medicinal chemistry letters.

[13]  Mohammad Nur-E-Alam,et al.  Optimizing natural products by biosynthetic engineering: discovery of nonquinone Hsp90 inhibitors. , 2008, Journal of medicinal chemistry.

[14]  J. Chmielewski,et al.  Scaffolds for blocking protein-protein interactions. , 2007, Current topics in medicinal chemistry.

[15]  Brian O. Bachmann,et al.  A genomics-guided approach for discovering and expressing cryptic metabolic pathways , 2003, Nature Biotechnology.

[16]  Irwin Hollander,et al.  Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. , 2002, Bioconjugate chemistry.

[17]  Paul A Wender,et al.  Function-oriented synthesis, step economy, and drug design. , 2008, Accounts of chemical research.

[18]  Micheal C. Wilson,et al.  The Discovery of Salinosporamide K from the Marine Bacterium “Salinispora pacifica” by Genome Mining Gives Insight into Pathway Evolution , 2011, Chembiochem : a European journal of chemical biology.

[19]  R. Morphy,et al.  Designed multiple ligands. An emerging drug discovery paradigm. , 2005, Journal of medicinal chemistry.

[20]  R. Babine,et al.  FKBP immunophilin patents for neurological disorders , 2005 .

[21]  Laurent Ducry,et al.  Antibody-drug conjugates: linking cytotoxic payloads to monoclonal antibodies. , 2010, Bioconjugate chemistry.

[22]  Christopher L. McClendon,et al.  Reaching for high-hanging fruit in drug discovery at protein–protein interfaces , 2007, Nature.

[23]  Christophe Corre,et al.  Identification of a bioactive 51-membered macrolide complex by activation of a silent polyketide synthase in Streptomyces ambofaciens , 2011, Proceedings of the National Academy of Sciences.

[24]  M. Smanski,et al.  Improvement of secondary metabolite production in Streptomyces by manipulating pathway regulation , 2010, Applied Microbiology and Biotechnology.

[25]  B. Shen,et al.  Polyketide synthase chemistry does not direct biosynthetic divergence between 9- and 10-membered enediynes , 2010, Proceedings of the National Academy of Sciences.

[26]  Melvin J. Yu,et al.  In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. , 2001, Cancer research.

[27]  Claes Gustafsson,et al.  Semi-synthetic DNA shuffling of aveC leads to improved industrial scale production of doramectin by Streptomyces avermitilis. , 2005, Metabolic engineering.

[28]  M. Poulter,et al.  Neuroimmunophilins: A novel drug therapy for the reversal of neurodegenerative disease? , 2004, Neuroscience.

[29]  Stuart L. Schreiber,et al.  Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes , 1991, Cell.

[30]  W. A. van der Donk,et al.  Genome mining for ribosomally synthesized natural products. , 2011, Current opinion in chemical biology.

[31]  M. Smanski,et al.  Engineered Streptomyces platensis Strains That Overproduce Antibiotics Platensimycin and Platencin , 2009, Antimicrobial Agents and Chemotherapy.